OBJECTIVES: This study aimed to evaluate the cost-effectiveness of upadacitinib in patients with moderately to severely active ulcerative colitis (UC), who have had an inadequate response, lost response, or were intolerant to either conventional therapy (bio-naive) or a biologic agent (bio-exposed), in Greece. METHODS: A cost-effectiveness model, consisting of an 8-week decision tree model (induction period) and a long-term Markov state-transition model with a 4-week cycle length (maintenance period), was locally adapted from a public payer perspective over the patient's lifetime. Upadacitinib was compared with other UC marketed biologics and small molecule agents in Greece. Clinical and utility data were retrieved from published literature. Direct costs pertaining to drug acquisition, administration, disease management, and adverse events were considered in the analysis. All cost inputs were indexed to 2023 euros. Model outcomes were patients' quality-adjusted life-years (QALYs), total costs, and incremental cost-effectiveness ratios (ICERs). RESULTS: In the bio-naive population, compared with adalimumab, golimumab, infliximab, ozanimod, tofacitinib, ustekinumab, and vedolizumab, upadacitinib was found to be more effective (QALY gains: 0.833, 0.670, 0.671, 0.783, 0.314, 0.577, and 0.522, respectively) and cost-effective (ICERs: euro18 618, euro21 682, euro17 864, euro15 637, euro30 061, euro12 776, and euro16 263, respectively). In the bio-exposed population, compared with adalimumab, ozanimod, tofacitinib, ustekinumab, and vedolizumab, upadacitinib demonstrated again a more effective (QALY gains: 0.784, 0.697, 0.514, 0.723, and 0.719, respectively) and cost-effective profile (ICERs: euro16 396, euro13 661, euro17 074, euro10 975, and euro13 881, respectively). CONCLUSIONS: Upadacitinib was estimated to be the most effective and cost-effective treatment among all advanced treatments for moderately to severely active UC in Greece.